crossing96/oncoscreening huggingface dataset:
Expression of Glucocorticoid Receptor and FOXO1/phospho-FOXO1 in Bladder Cancer as Independent Prognosticators.	BACKGROUND/AIM: Cross-talk between forkhead box O1 (FOXO1), a transcriptional factor known to function as a tumor suppressor via the PI3K/AKT pathway, and glucocorticoid receptor (GR) has been implied in non-urothelial cells. The present study aimed to investigate the association of FOXO1 and GR expression in bladder cancer and its prognostic significance. MATERIALS AND METHODS: Immunohistochemical staining for GR, FOXO1, and p-FOXO1 (a phosphorylated/inactivated form) was performed in a set of bladder cancer tissue microarray comprising 50 low-grade non-invasive tumors, 28 high-grade non-muscle-invasive tumors, and 51 high-grade muscle-invasive tumors. Western blotting for FOXO1 and p-FOXO1 was also conducted in human bladder cancer cells. RESULTS: GR expression was detected in 109 [84.5%; 39 (30.2%) weakly positive (1+), 39 (30.2%) moderately positive (2+), 31 (24.0%) strongly positive (3+)] tumors, whereas FOXO1 and p-FOXO1 were immunoreactive in 17 [13.2%; 16 (12.4%) 1+, 1 (0.8%) 2+] and 71 [55.0%; 57 (44.2%) 1+, 14 (10.9%) 2+] tumors, respectively. The expression levels of GR were positively and negatively correlated with those of FOXO1 (p=0.003) and p-FOXO1 (p=0.009), respectively. GR(0/1+)/FOXO1(0) and GR(0/1+)/p-FOXO1(1+/2+) were significantly more often observed in high-grade (vs. low-grade) or muscle-invasive (vs. non-muscle-invasive) tumors. Both univariate and multivariate analyses revealed that GR(0/1+)/FOXO1(0) and GR(0/1+)/p-FOXO1(1+/2+) were associated with a significantly higher risk for the recurrence of non-invasive disease or progression of muscle-invasive disease. In 2 GR-positive bladder cancer lines, glucocorticoids (i.e., dexamethasone, prednisone) and a GR antagonist (i.e., RU486) induced the levels of FOXO1 and p-FOXO1 expression, respectively. CONCLUSION: The expression levels of GR and FOXO1 or p-FOXO1 were strongly correlated in bladder cancer. Specific GR/FOXO1 and GR/p-FOXO1 expression profiles served as independent predictors of disease recurrence or progression.	bladder
Pioglitazone Suppresses Urothelial Tumorigenesis In Vitro: A Potential Chemopreventive Agent.	BACKGROUND/AIM: Pioglitazone (PIO), a peroxisome proliferator-activated receptor gamma agonist, is typically used to treat type 2 diabetes mellitus. In addition to its metabolic effects, PIO exhibits various biological activities, including potential anticancer effects. However, its efficacy and mechanistic relevance in the development and progression of cancer, including urothelial carcinoma, remain unclear. Herein, we investigated the functional impact of PIO on urothelial tumorigenesis. MATERIALS AND METHODS: An in vitro urothelial neoplastic transformation model was established by inducing SV-HUC-1 cells with a chemical carcinogen 3-methylcholanthrene. This model was used to investigate the effects of PIO on neoplastic/malignant transformation. RESULTS: PIO significantly inhibited the neoplastic/malignant transformation of SV-HUC-1 cells. Moreover, PIO treatment up-regulated tumor suppressors, including p53 and phosphatase and tensin homolog (PTEN), as well as the epithelial marker E-cadherin, while down-regulating the mesenchymal marker N-cadherin and the oncogenic factor nuclear factor kappa B (NF-κB), as confirmed by protein and mRNA expression analyses. CONCLUSION: PIO has a chemopreventive effect on urothelial tumorigenesis, supporting its potential use as a preferred anti-diabetic agent for patients with a risk or history of urothelial carcinoma.	bladder
Tumor-derived lactate fuels the STAT3-LCN2 pathway to promote bladder cancer malignancy and chemoresistance.	Bladder cancer progression is closely linked to metabolic changes within the tumor microenvironment (TME), particularly elevated lactate levels. Lipocalin 2 (LCN2), a protein involved in iron regulation, has been implicated in tumor progression in several cancers, but its regulatory mechanisms and role in bladder cancer remain unclear. Bladder cancer cell lines were treated with exogenous lactate or subjected to inhibition of endogenous lactate production to evaluate changes in LCN2 expression. The role of Signal Transducer and Activator of Transcription 3 (STAT3) was assessed using genetic knockdown and pharmacological inhibitors. Functional assays including migration, epithelial-to-mesenchymal transition (EMT), sphere formation, and stemness marker analysis were performed to determine the biological effects of LCN2. Chemoresistance to gemcitabine was examined with and without LCN2 silencing. Clinically, LCN2 expression was significantly associated with the pathological relevance of bladder tumors. Lactate significantly induced LCN2 expression in bladder cancer cells through activation of STAT3. Disruption of STAT3 signaling reduced LCN2 levels. High LCN2 expression correlated with advanced tumor grade, poor prognosis, and shorter overall survival. Functionally, LCN2 promoted EMT, enhanced cell migration, and increased stem cell-like properties, as evidenced by elevated stemness markers and sphere-forming ability. Moreover, lactate-induced LCN2 expression conferred resistance to gemcitabine treatment, while LCN2 knockdown restored chemosensitivity. This study identifies tumor-derived lactate as a key inducer of LCN2 expression via STAT3 activation in bladder cancer. LCN2 contributes to tumor aggressiveness, cancer stemness, and chemoresistance. Targeting the STAT3-LCN2 signaling axis may offer a promising therapeutic strategy to suppress bladder cancer progression and overcome treatment resistance within a lactate-rich TME.	bladder
Multi-institutional validation of AI models for classifying urothelial neoplasms in digital pathology.	This study proposes a deep learning approach for classifying normal, noninvasive, and invasive urothelial neoplasms via digitized histopathologicalimages. Despite many artificial intelligence (AI) models for cancer diagnosis, few focus on bladder lesions or differentiate between these critical categories. We developed convolutional neural networks (CNNs) and transformer-based models, which were trained on 12,500 whole-slide images (WSIs) from five institutions, with preprocessing steps including stain normalization and patch extraction. Fivefold cross-validation was used for evaluation against expert-annotated labels. Among tested models, EfficientNet-B6 achieved the highest performance, with an accuracy of 0.913 (95% confidence interval (CI), 0.907-0.920), sensitivity of 0.909 (95% CI, 0.904-0.914), specificity of 0.956 (95% CI, 0.953-0.960), F1-score of 0.906 (95% CI, 0.901-0.911), and an area under the receiver operating characteristic curve (AUC) of 0.983 (95% CI, 0.982-0.984). These results demonstrate the effectiveness and generalizability of AI-based bladder cancer classification.	bladder
Survival patterns after perioperative treatment escalation and cystectomy for synchronous oligometastatic bladder cancer (M1a/M1b) - a population-based series.	BACKGROUND: The role of cystectomy in synchronous oligometastatic bladder cancer is unclear. OBJECTIVE: To describe a population-based consecutive cohort with primary oligometastatic bladder cancer (M1a or M1b) treated with curative intent.  Methods: Twenty consecutive patients with primary stage M1a or M1b bladder cancer subjected to induction chemotherapy and radical cystectomy 2013-2024 in the Southern healthcare region were identified in the Swedish National Register for Urinary Bladder Cancer. Primary staging and the evaluation of response to systemic induction chemotherapy were performed using [18F]fluorodeoxyglucose positron emission tomography with computed tomography (FDG PET-CT). After additional chemotherapy, consolidating radical cystectomy, lymphadenectomy and in selected patients, postoperative stereotactic radiotherapy or adjuvant nivolumab were applied. Disease-free survival (DFS) and overall survival (OS) from chemotherapy start were visualised by Kaplan-Meier curves. Results: Ten patients with retroperitoneal lymph node metastases, seven with single bone metastasis and three with inguinal metastases responding on three chemotherapy courses according to FDG PET-CT-evaluations were subjected to additional chemotherapy and subsequent radical cystectomy and lymphadenectomy with templates including lymph node metastases. Five patients with bone-oligometastatic disease received consolidating stereotactic radiotherapy, and three patients received adjuvant nivolumab. Postoperatively, one patient progressed in preoperatively known bone metastasis, and one patient displayed lack of chemotherapy response in the cystectomy specimen and was consequently subjected to second-line pembrolizumab treatment with palliative intent. At a median follow-up of 23 months, 10  patients (50%) were disease-free. CONCLUSIONS: Long-term survival was observed in some individuals after multimodal treatment for selected patients with synchronous oligometastatic bladder cancer. PATIENT SUMMARY: Amongst patients diagnosed with limited number of distant bladder cancer metastases, those responding on initial systemic chemotherapy can be selected for further treatment. After additional chemotherapy, radical cystectomy with lymphadenectomy and individually intensified treatment with consolidating radiation towards distant metastases and/or adjuvant systemic treatment with checkpoint inhibitors for 12 months, long-term survival was observed in some individuals despite a disease-entity with bad prognostic features.	bladder
Synergistic Anticancer Effects of COL6A1 Downregulation and the PD1 Inhibitor Pembrolizumab in Bladder Cancer.	Immunotherapy has shown remarkable efficacy in treatment of bladder cancer. Collagen type VI alpha 1 (COL6A1) is found to be linked to response to immunotherapy of programmed cell death protein 1 (PD1) checkpoint inhibitors. This study elucidated the critical role of COL6A1 in regulating immune escape and response to the PD1 inhibitor pembrolizumab. Expression analysis was performed by quantitative PCR, western blotting, and immunohistochemistry. Cell in vitro functions were evaluated by detecting cell proliferation, invasion, migration, and apoptosis. Xenograft assays were used to define the role of COL6A1 in vivo. CD8(+) T cells were co-cultured with treated T24 and J82 cells to analyze the impact of COL6A1 knockdown and pembrolizumab on cell immune response. High COL6A1 expression was observed in bladder cancer tissues and cells. COL6A1 downregulation inhibited bladder cancer cell proliferation, invasion, and migration and induced cell apoptosis. Moreover, COL6A1 knockdown reduced the apoptosis of CD8(+) T cells and reduced the expression of PD-L1. Knockdown of COL6A1 also suppressed bladder cancer tumor growth in vivo. Pembrolizumab inhibited bladder cancer cell proliferation, invasion, and migration and attenuated CD8(+) cell apoptosis. Importantly, COL6A1 downregulation enhanced the therapeutic efficacy of pembrolizumab on bladder cancer cell malignant progression and immune escape. Combination of COL6A1 downregulation and pembrolizumab synergistically suppressed bladder cancer cell growth and metastasis, providing the possibility of inhibiting bladder cancer progression.	bladder
Natural lignan justicidin A-induced mitophagy as a targetable niche in bladder cancer.	Accumulated dysfunctional mitochondria are involved in tumorigenesis, and it is conceivable that mitophagy, a selective form of autophagic degradation of mitochondria, plays a tumor-suppressive role. Our bioinformatics analysis identified lignan justicidin A (JA) as a potential mitophagy inducer. In HRAS-mutant human bladder cancer T24 cells, JA reduced population cell growth, changed mitochondrial membrane potential, and induced autophagy. JA-induced mitophagy was demonstrated by a reduction of mitochondrial puncta by confocal microscopy and co-localization of autophagy marker LC3 and mitochondrial matrix protein HSP60 in the autophagic vesicles by electron microscopy. These phenomena were associated with altered mitochondrial dynamics, increased expressions of HIF-1α and its target gene BNIP3, and induced co-immunoprecipitation of LC3 with BNIP3 homo-dimer. Confocal microscopy further observed co-localizations among puncta of LC3, BNIP3, and HSP60. JA raised BNIP3 expression in T24 but not E7 (HRAS wild-type) and induced stronger autophagy in T24 than in E7 cells, indicating JA preferentially caused BNIP3-mediated mitophagy in urinary tract cells with oncogenic HRAS. Furthermore, JA enhanced cytotoxicity of T24 cells to anti-cancer drugs cisplatin combined with gemcitabine. Analyses of patients' data further showed that, in contrast to other major cancer types, lowered mitophagy in bladder urothelial carcinoma compared with normal tissues and reduced expression of mitochondrial genes in cisplatin-responsive bladder cancer cells compared with non-responsive cells suggest mitophagy acts as a tumor suppressor to avoid cisplatin resistance in bladder cancer. Overall, our data suggest the role of BNIP3 and mitophagy in anti-cancer mechanism of human bladder cancer with HRAS mutation in response to JA.	bladder
Vesicocolic fistula in myasthenia gravis patient: A case report.	RATIONALE: Vesicocolic fistula is a rare disease, and surgical intervention is the only available treatment, while complications can arise when patients also suffer from myasthenia gravis, a neuromuscular disease that can be exacerbated by the stress of surgery. PATIENT CONCERNS: We report a 60-year-old male with a history of heart disease, myasthenia gravis, and other comorbidities who was admitted with complaints of fecaluria for the past 18 months. DIAGNOSES: Computed tomography showed bladder cancer involving the distal descending colon, with a high suspicion of a vesicocolic fistula. In addition, multiple diverticula were observed in both the descending and sigmoid colon. INTERVENTIONS: In this case, a multidisciplinary approach and careful perioperative management enabled the successful resolution of the fistula while minimizing risks associated with the patient's underlying condition. Finally, the fistula was successfully solved by laparoscopic surgery. OUTCOMES: At 3 months postoperatively, the patient recovered well and did not reappear with the previous symptom. LESSONS: Vesicocolic fistula complicated by myasthenia gravis poses unique challenges in surgical management. We summarized the clinical features and treatment methods of this vesicocolic fistula, hoping to contribute to the development of the surgical treatment strategies for vesicocolic fistula and provide insights for others experiencing similar conditions.	bladder
Urinary Aromatic Amine Exposures in Pet Dogs With Urothelial Carcinoma and Unaffected Controls.	Urothelial carcinoma (UC) in pet dogs resembles muscle-invasive UC in people. Human UC is strongly associated with aromatic amine exposures, either in tobacco smoke or through occupational exposures. However, the role of aromatic amines in canine UC is not understood. Urine from dogs diagnosed with UC (n = 37) and unaffected controls (n = 36), collected in a previous case-control study, were analysed for 12 aromatic amines. Eleven aromatic amines were (o-anisidine, p-toluidine, o-toluidine, 4-chloroaniline, 2,6-dimethylaniline, 3,5-dimethylaniline, aniline, 2-napthylamine, p-cresidine, 4,4'-methylenedianiline, and 4-ethoxyaniline) detected in most urine samples; 4-aminobiphenyl was detected in only three dogs. Urinary concentrations of o-toluidine were significantly higher in cases (median 0.16, range 0.03-2.00 ng/mg creat) versus controls (median 0.11, range 0.02-0.42 ng/mg/creat; p = 0.017), but differences were modest with substantial overlap between groups, and we did not control for multiple comparisons. Urinary o-toluidine was most strongly correlated with urinary aniline, which reached the highest median concentrations overall (1.65 ng/mg creat or 2.60 ng/mL). Total molar aromatic amine urinary exposures were not different between pet dogs living in metropolitan versus rural areas using USDA Rural-Urban Continuum codes in this small sample size. Follow-up studies are indicated to establish the genotoxic thresholds for o-toluidine and aniline in canine urothelial cells and determine whether some pet dogs are exposed to genotoxic urinary concentrations of these aromatic amines in vivo.	bladder
Revisiting BCG: The potential of rescue BCG therapy for BCG-unresponsive non-muscle-invasive bladder cancer.	OBJECTIVE: To evaluate the role of Rescue BCG in the treatment of BCG-unresponsive nonmuscle-invasive bladder cancer (NMIBC), in order to inform clinical decision-making especially when access to alternative therapies is limited. METHODS: From an institutional database, patients who met the criteria of BCG-unresponsive NMIBC between 2002 and 2023 were identified and sorted into 2 cohorts: those who received additional BCG therapy immediately after BCG-unresponsive designation and those who received alternative treatments such as intravesical chemotherapy and radical cystectomy. Primary endpoint was progression-free survival (PFS). Secondary endpoints included high-grade (HG) recurrence-free survival (RFS) and overall survival (OS). RESULTS: A total of 120 patients with BCG-unresponsive NMIBC were evaluated. Of these, 66 received Rescue BCG, and 54 did not. Both cohorts were similar in demographics, although the Rescue BCG cohort had significantly more HG T1 disease. The 1-year PFS for Rescue BCG was 95.3% compared with 84.5% for No Rescue BCG (log rank, P = 0.4). Multivariable analyses showed Rescue BCG significantly reduced disease progression (HR: 0.38, 95% CI, 0.14-0.99) and improved overall survival (HR: 0.18, 95% CI, 0.04-0.79), though no difference in HG recurrence was found. Limitations include retrospective design. CONCLUSION: Use of rescue BCG was associated with reduced risk of progression and improved overall survival when compared to No Rescue BCG. There was no significant difference in PFS between the No Rescue BCG cohort and in patients who had a HG recurrence within 2 years of being treated with Rescue BCG suggesting that a trial of Rescue BCG does not compromise overall oncologic outcomes.	bladder
Prognostic difference of molecular subtypes in non-muscle invasive bladder cancer.	In recent years, 2 molecular types have been defined in urothelial carcinoma, as luminal and basal. The molecular subtyping is generally based on genetic studies in non-muscle invasive bladder cancer (NMIBC) however the studies with immunohistochemical reflection of this subtyping in NMIBC is limited. In our study, we aimed to use GATA3 and keratin 5/6 for subtyping of NMIBC, and to investigate the follow-up results. Materials and methods: Patients who underwent transurethral resection for the first time and whose final diagnosis was reported as NMIBC were prospectively included. A block representing the tumor was stained with GATA3 and keratin 5/6.The relationships between the subtypes and demographic data, recurrence rates, and time to recurrence were evaluated. A total of 100 patients diagnosed with NMIBC were included. The keratin 5/6 negativity was 64% and all of these patients were GATA3 positive. The keratin 5/6 positivity was 36%. None of the age, tumor size, lamina propria invasion, keratin 5/6 and GATA3 positivity were significant for predicting the risk of recurrence. The mean time to recurrence was 283 days and 332 days in the keratin 5/6 positive and negative group, respectively but the relation was not statistically significant. Molecular classification is difficult due to technical reasons, but it can be performed with GATA3 and keratin 5/6 by immunohistochemistry. New studies are needed to determine the clinical differences and to specialize the management of bladder tumors.	bladder
CDH11 Contributes to Bladder Cancer Progression via Regulation of Mitochondrial Energy Metabolism.	BACKGROUND: Approximately 83,000 new cases of bladder cancer (BC) in the United States and 23,000 in Japan are confirmed per year, and the number of new BC cases increases every year. While the prognosis for localized cancer is favorable, treatment options for metastatic cancer are limited, and the prognosis is extremely poor. AIM: Although the prevention of metastasis and the development of novel treatments for metastatic cancer are urgent challenges, the molecules contributing to BC metastasis and prognosis remain largely unknown. This study aimed to identify and analyze novel therapeutic target molecules for metastatic BC. MATERIALS AND METHODS: We collected gene expression datasets for BC cell lines from Gene Expression Omnibus and selected genes highly expressed in advanced BC cell lines. We also extracted genes highly expressed in metastatic BC patients from The Cancer Genome Atlas. We performed integrated analysis on these genes and combined it with Kaplan-Meier analysis to identify genes involved in BC progression. The results revealed that CDH11 is involved in bladder cancer progression. We established CDH11 knockdown (KD) using shRNA in advanced bladder cancer cell lines and performed analyses of cell proliferation, invasion, and migration; gene expression analysis via RNA-seq; tumor formation via xenografts; metabolic analysis using the Flux analyzer; and therapeutic effect analysis using low-molecular-weight compounds. RESULTS: While CDH11 KD did not alter cell proliferation, invasion, or migration in vitro, CDH11 KD significantly suppressed tumor growth in an in vivo subcutaneous xenograft mouse model. RNA-seq revealed that CDH11 KD cells decreased the expression of genes related to mitochondrial metabolism, and a metabolic flux analyzer confirmed decreased mitochondrial activity in the KD cells. Furthermore, use of a CDH11 inhibitor resulted in decreased mitochondrial activity in vitro, and CDH11 inhibitor resulted in inhibition of tumor growth in vivo. DISCUSSION: Our findings suggest that CDH11 is highly expressed in advanced BC and may regulate the TME by interacting with other cell types and regulating mitochondrial energy metabolism. CONCLUSION: These results suggest that CDH11 is involved in BC progression and is a potential therapeutic target.	bladder
Oncological outcomes for patients with European Association of Urology definitions of BCG failure treated with radical cystectomy.	INTRODUCTION: The management of non-muscle invasive bladder cancer (NMIBC) failing Bacillus Calmette-Guérin (BCG) therapy remains challenging. The European Association of Urology (EAU) has standardized definitions of BCG failure. We aim to evaluate oncological outcomes in patients undergoing radical cystectomy (RC) for NMIBC following BCG failure, as defined by the EAU. METHODS: Retrospective study analyzed 93 patients with NMIBC who underwent RC between 2011 and 2021 after BCG therapy failure. Patients were stratified into 4 groups: clinical NMIBC, clinical progression, subclinical progression (understaged), and pathological NMIBC (pNMIBC) groups. Oncological outcomes included cancer-specific survival (CSS) and overall survival (OS). Kaplan-Meier and logistic regression analyses were used to evaluate outcomes and predictors of disease progression. RESULTS: Among 93 patients, 64 (68.8%) had clinical NMIBC, and 29 (31.2%) showed clinical progression to muscle-invasive bladder cancer (MIBC) prior to RC. Of those with clinical NMIBC, 46 (71.9%) were confirmed as pNMIBC and 18 (28.1%) had subclinical progression. Patients with pNMIBC had significantly better 5-year CSS (95.5%) and OS (77.6%) compared to those with clinical (CSS 70.4%, OS 50.2%) or subclinical progression (CSS 64.1%, OS 43.8%). cT1 with conco-mitant carcinoma in situ and prostatic urethral involvement were independent predictors of muscle-invasive disease at RC. CONCLUSIONS: Patients treated at an appropriate stage show superior survival outcomes com-pared to those with progression. These findings underscore the importance of timely surgical intervention in BCG-unresponsive NMIBC and support early RC in select high-risk patients to improve long-term prognosis.	bladder